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. 2025 Apr 25:16:1550133.
doi: 10.3389/fphar.2025.1550133. eCollection 2025.

Assessment of potential drug-drug interactions in patients with hereditary angioedema from the ITACA cohort: simulations from a real-life dataset considering danazol versus berotralstat

Andrea Zanichelli #  1   2 , Dario Cattaneo #  3 , Antonio Gidaro #  4 , Riccardo Senter  5 , Francesco Arcoleo  6 , Pietro Accardo  6 , Donatella Bignardi  7 , Paolo Borrelli  8 , Caterina Colangelo  9 , Tiziana De Pasquale  10 , Davide Firinu  11 , Francesca Perego  12 , Massimo Triggiani  13 , Giuseppe Spadaro  14 , Chiara Cogliati  4 , Emanuele Bizzi  15 , Valentina Popescu Janu  4 , Maria Domenica Guarino  16 , Paolina Quattrocchi  17 , Luisa Brussino  18 , Oliviero Rossi  19 , Paola Triggianese  20 , Stefano Agolini  21 , Francesco Giardino  22 , Vincenzo Montinaro  23 , Mauro Cancian  5
Affiliations

Assessment of potential drug-drug interactions in patients with hereditary angioedema from the ITACA cohort: simulations from a real-life dataset considering danazol versus berotralstat

Andrea Zanichelli et al. Front Pharmacol. .

Abstract

Background: Danazol is regularly used as a prophylactic treatment in patients with Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH). However, this drug is characterized by a risk of drug-drug interactions (DDIs). Berotralstat, the first oral kallikrein inhibitor, has been recently approved for the prevention of HAE attacks. Here, we sought to compare the risk of potential DDIs in real-life HAE patients hypothetically given Danazol or Berotralstat.

Methods: Our clinic's database was retrospectively reviewed to identify patients diagnosed with HAE who were treated with at least one concomitant medication. The DDIs were assessed using three freely available drug interaction checkers and scored based on their severity. The agreement between the three drug checkers was evaluated using weighted Cohen's kappa coefficient.

Results: 75 HAE patients (64% female, mean age 56 ± 21 years) were considered. They were mainly treated with antihypertensives (37%), hypoglycemic (19%), and hypolipemic agents (17%). Significant discrepancies among the three-drug interaction checkers were found. The first checker identified 18 potential DDIs, all involving Danazol and a statin (simvastatin). The second checker identified, respectively, 66 and 14 DDIs for Danazol (20% severe, regarding Simvastatin and Rivaroxaban) and Berotralstat (0% severe). The third checker identified 49 and 43 DDIs for Danazol (22% severe, regarding Simvastatin) and Berotralstat (0%).

Conclusion: Berotralstat was consistently associated with a reduced risk of DDIs compared with Danazol. A rational assessment of DDIs would help select the best prophylactic treatment for HAE.

Keywords: C1-inhibitor deficiency, drug-drug interactions; ITACA; berotralstat; bradykinin; danazol; hereditary angioedema; long-term prophylaxis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

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